Manifestaciones de Esclerosis Sitémica

Aca va lo de esclerosis Overview of the clinical manifestations of systemic sclerosis (scleroderma) in adults Author John Varga, MD Section Editor John S Axford, DSc, MD, FRCP Deputy Editor Paul L Romain, MD Last literature review version 16.3: octubre 2008 This topic last updated: agosto 19, 2008 (More) INTRODUCTION — The term scleroderma, is used to describe the presence of thickened, hardened skin (from the Greek "scleros") [1]. Scleroderma is the hallmark feature of a heterogeneous group of conditions, the classification of which is discussed in more detail separately. (See "Classification of scleroderma disorders"). To summarize briefly, scleroderma may be a clinical feature of limited anatomic extent affecting only the skin and adjacent tissues or it may be associated with systemic involvement. When the characteristic skin disorder is associated with internal organ involvement, the disease is termed systemic sclerosis (SSc). SSc is subcategorized further into diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) on the basis of the extent and distribution of skin involvement. LcSSc is generally associated with the CREST syndrome (see "Limited cutaneous SSc" below) [2]. Other disorders that may either have typical scleroderma skin changes or those that have scleroderma-like cutaneous involvement are considerations in the differential diagnosis of SSc. (See "Diagnosis and differential diagnosis of systemic sclerosis (scleroderma) in adults"). The manifestations of SSc are diverse. Most prominent are abnormalities of the circulation (most notably Raynaud phenomenon) and involvement of multiple organ systems, including the musculoskeletal, renal, pulmonary, cardiac, and gastrointestinal systems, with fibrotic and/or vascular complications. The prevalence rates of diseases that share scleroderma as a clinical feature are reported to range from 4 to 489 cases per million individuals [3,4]. Incidence figures for SSc are 0.6-122 per million persons/year; the actual prevalence is probably at the high end of the range noted above [4]. There are regional differences in incidence, as examples: higher rates are seen in the United States and Australia than in Japan or Europe and higher rates in blacks than whites [4]. A brief overview of the characteristic sclerodermatous skin changes and of other organ involvement in adults is presented here. The pathogenesis, diagnosis, and treatment of SSc are discussed separately. (See "Pathogenesis of systemic sclerosis (scleroderma)", and see "Diagnosis and differential diagnosis of systemic sclerosis (scleroderma) in adults", and see "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults"). Localized forms of scleroderma, and scleroderma in childhood are discussed separately. (See "Localized scleroderma in childhood"). SKIN INVOLVEMENT — Skin involvement is characterized by variable thickening and hardening of the skin. The fingers, hands and face are generally the earliest areas of the body involved. Edematous swelling and erythema of the skin may precede skin induration. Other prominent skin manifestations include: • Pruritus in the early stages • Edema in the early stages • Sclerodactyly • Digital ulcers • Pitting at the fingertips • Telangiectasia • Calcinosis cutis The assessment of skin involvement includes semiquantitative estimation of skin thickness, pliability (hardness), and fixation or tethering to underlying structures (tethering). The modified Rodnan skin score, commonly used in clinical trials, score the severity of these features in 17 distinct areas of the body from 0 (normal) to 3 (most severe). Objective approaches to measuring skin disease, such as ultrasonography [5,6], and use of a durometer, are under investigation. The distribution of skin lesions and the accompanying pattern of internal organ involvement forms the basis for the current classification system of SSc into limited and diffuse forms of the disease (show table 1 and show table 2). (See "Classification of scleroderma disorders"). Radiographs of the hands may reveal calcinosis and resorption of the distal phalangeal tufts (acro-osteolysis); articular erosions, joint space narrowing, and demineralization are other radiographic findings that may be present [7]. Limited cutaneous SSc — Patients with limited cutaneous SSc (lcSSc) typically have skin sclerosis restricted to the hands, and to a lesser extent, the face and neck. With time some patients develop scleroderma of the distal forearm. Patients with limited cutaneous SSc generally have prominent vascular manifestations, including severe Raynaud phenomenon and cutaneous telangiectasia. Many of these patients have other manifestations of what has been referred to as the CREST syndrome (Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia). Diffuse cutaneous SSc — Sclerotic skin on the chest, abdomen, or upper arms and shoulders is indicative of diffuse cutaneous SSc (dcSSc). Patients with dcSSc are more likely to have, or to develop, internal organ damage due to ischemic injury or fibrosis than those with lcSSc. Systemic sclerosis sine scleroderma — Not all patients with SSc have skin manifestations. SSc sine scleroderma, is characterized by typical vascular and/or fibrotic features of systemic disease (eg, renal crisis, pulmonary hypertension, or interstitial lung disease) but without clinically evident skin sclerosis. VASCULAR DISEASE — The most obvious clinical manifestation of vascular dysfunction is Raynaud phenomenon, defined as sequential color changes in the digits precipitated by cold, stress or even change in temperatures. Raynaud phenomenon is due to arterial vasoconstriction in the digits. The color changes of pallor ("white"), acrocyanosis ("blue"), and reperfusion hyperemia ("red") are characteristic. (See "Clinical manifestations and diagnosis of the Raynaud phenomenon"). Vascular injury and subsequent chronic damage underlies other serious complications of SSc, including pulmonary artery hypertension, scleroderma renal crisis and gastric antral vascular ectasia, and also contributes to the pathogenesis of cardiac and gastrointestinal complications. Raynaud phenomenon — Although Raynaud phenomenon is classically viewed as reversible vasospasm, many patients with SSc develop progressive structural changes in the small blood vessels, with permanently impaired flow. Episodes of Raynaud phenomenon may be prolonged and can result in digital ulceration or infarction. It is important to realize that persons presenting with Raynaud phenomenon may have primary (no definable underlying disease) or secondary Raynaud phenomenon. Whereas Raynaud phenomenon is seen in SSc, other connective tissue diseases, or a number of disorders which result in abnormal blood flow (show table 3), primary Raynaud phenomenon is common in the general population, occurs in otherwise healthy individuals, and almost always has a benign course. In patients with lcSSc, Raynaud phenomenon generally precedes other disease manifestations, sometimes by years or even decades. In contrast, in patients with dcSSc, the onset of Raynaud phenomenon generally coincides with, or may even follow, the appearance of characteristic skin or musculoskeletal manifestations. ORGAN INVOLVEMENT — Extracutaneous organ involvement is common in SSc. The lungs, kidneys, gastrointestinal tract, and heart are commonly affected (show table 4). Gastrointestinal involvement — Nearly 90 percent of patients with either subtype of SSc (dcSSc or lcSSc) have some degree of gastrointestinal involvement [8,9]. Nearly half of these patients may be asymptomatic. Esophageal hypomotility and incompetence of the lower esophageal sphincter disease was the earliest visceral manifestation of SSc described. Symptoms principally result from chronic gastroesophageal reflux, with subsequent chronic esophagitis and stricture formation, and abnormal motility. Any part of the gastrointestinal tract from mouth to anus may be affected. Thus, a variety of signs and symptoms are seen in patients with SSc, including dysphagia ad choking, heartburn, cough after swallowing, bloating, alternating constipation and diarrhea, pseudo-obstruction and bacterial small bowel overgrowth with malabsorption, and fecal incontinence. Chronic gastroesophageal reflux and recurrent episodes of aspiration may contribute to the development of interstitial lung disease [10]. Vascular ectasia in the stomach ("watermelon stomach") is frequent, and may cause chronic gastrointestinal bleeding and anemia. (See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)"). Pulmonary disease — Pulmonary involvement is seen in more than 70 percent of patients with SSc. The two principal clinical manifestations of lung involvement are interstitial lung disease (also called fibrosing alveolitis or pulmonary fibrosis) and pulmonary vascular disease, leading to pulmonary arterial hypertension (show table 5). These issues are discussed in detail separately but will be briefly reviewed here. (See "Clinical manifestations of systemic sclerosis (scleroderma) lung disease"). Interstitial lung disease — Some degree of interstitial lung disease occurs in more than three-quarters of patients with SSc. Fibrosis is commonly preceded by alveolitis. The most common symptoms are breathlessness on exertion (which may progress to dyspnea at rest), and a nonproductive cough. Chest pain is infrequent and hemoptysis is rare. On examination, auscultation over the lungs reveals fine "Velcro" rales most prominent at the lung bases. Pulmonary vascular disease — Pulmonary vascular disease occurs in 10 to 40 percent of patients with SSc, and is more common in patients with limited cutaneous disease. It may occur in the absence of significant interstitial lung disease, a setting it which it resembles idiopathic pulmonary hypertension. Dyspnea with exertion and diminished exercise tolerance are the most common initial symptoms of pulmonary arterial hypertension. Pulmonary arterial hypertension is generally a late complication of SSc, is typically progressive and, if severe, can lead to cor pulmonale and right-sided heart failure. (See "Cor pulmonale"). Thrombosis of the pulmonary vessels is a common complication of late-stage pulmonary arterial hypertension, and is a frequent cause of death. Lung cancer — The risk of lung cancer is increased in patients with SSc, and is similar in lcSSc and dcSSc. The incidence rate of malignant lung neoplasms is approximately five fold higher than for an age and gender matched subset of the general population. (See "Cancer risk" below). Renal disease — Autopsy studies suggest that 60 to 80 percent of patients with dcSSc have pathologic evidence of kidney damage [11,12]. Impaired renal reserve may be present in the absence of clinical renal disease [13]. Some degree of proteinuria, a mild elevation in the plasma creatinine concentration, and/or hypertension are observed in as many as 50 percent of patients [14,15]. Scleroderma renal crisis — Severe and life-threatening renal disease develops in approximately 10 to 15 percent of patients. This type of renal involvement is more frequent in patients with dcSSc than those with lcSSc. Scleroderma renal crisis is discussed in more detail separately. (See "Scleroderma renal crisis"). To summarize briefly, this form of renal involvement is characterized by: • Acute onset of renal failure • Urine analysis reveals only mild proteinuria with few cells or casts • Abrupt onset of moderate to marked or malignant hypertension (although some patients remain normotensive) Other features of scleroderma renal crisis may be due to the effects of severe hypertension or vasculopathy and include: microangiopathic hemolytic anemia, pulmonary edema, headache, blurred vision, and hypertensive encephalopathy, often complicated by generalized seizures. Cardiac disease — Patients with symptomatic cardiac involvement due to SSc have a poor prognosis, with two and five year mortality rates of approximately 60 and 75 percent, respectively [16]. Cardiac complications secondary to systemic or pulmonary hypertension are most common in SSc, but primary cardiac involvement also occurs. The manifestations of primary cardiac involvement include pericarditis, pericardial effusion, myocardial fibrosis, heart failure, myocarditis associated with myositis, conduction disturbances, and arrhythmias [16,17]. Pericardial disease — Symptomatic pericarditis occurs in 7 to 20 percent of patients with SSc, but pathologic evidence of pericardial involvement is observed in 70 to 80 percent at autopsy. Pericardial effusions may be small or large, and can develop rapidly. There is an association between pericardial effusion and the development of acute renal failure. Two potential explanations for this association have been suggested. First, pericardial effusion may simply be a marker of active and/or severe SSc. Second, the presence of a large pericardial effusion could compromise cardiac output, resulting in renal hypoperfusion, triggering a cascade of events culminating in scleroderma renal crisis. (See "Scleroderma renal crisis"). Myocardial disease — Patchy myocardial fibrosis is a hallmark of cardiac involvement in SSc [18]. It is distinguishable from the fibrosis associated with coronary atherosclerotic disease and is independent of the secondary cardiac involvement that may result from pulmonary hypertension. It is thought to result from recurrent vasospasm of small vessels (similar to Raynaud phenomenon), and is often associated with contraction band necrosis, a histological lesion indicative of myocardial ischemia followed by reperfusion. The degree of myocardial fibrosis may be increased in SSc patients with a long history of Raynaud phenomenon [18]. The myocardial disease can lead to systolic or more often diastolic ventricular dysfunction. This was illustrated in a Doppler echocardiography study of 570 patients with SSc in which left ventricular systolic and diastolic dysfunction were present in 1 and 18 percent, respectively [19]. Higher rates of myocardial dysfunction have been reported with tissue Doppler studies in which the abnormalities were independent of pulmonary artery hypertension or interstitial lung disease [20]. (See "Tissue Doppler echocardiography"). Arrhythmias — Conduction system disease and arrhythmias are common. They are likely to result from fibrosis of the myocardium and conduction system. Many deaths among SSc patients are sudden, some of which may result from a ventricular arrhythmia. Musculoskeletal disease — The earliest manifestations of diffuse SSc often are edema and swelling of the hands, arthralgia and myalgia. True inflammatory arthritis is uncommon in SSc. Joint pain, immobility and contractures develop as the result of fibrosis around tendons and other periarticular structures. Contractures of the fingers from this process are most common, but large joint contractures involving the wrists, elbows and ankles may also occur. The process is sometimes associated with palpable and/or audible deep tendon friction rubs. Tendon friction rubs occur predominantly in patients with dcSSc. The most common sites of involvement are the extensor and flexor tendons of the fingers and wrist, tendons over the elbow (triceps), knees (patellar), and ankle (anterior and posterior tibial, peroneal and Achilles). Some studies suggest that the presence of tendon friction rubs is a marker for aggressive disease and increased risk of developing internal organ involvement [21]. Deposits of hydroxyapatite crystals may occasionally be observed, with resultant severe joint damage. Destructive joint disease in a patient with SSc may suggest an overlap syndrome with rheumatoid arthritis. (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes"). Neuromuscular involvement — Neuromuscular involvement in SSc is discussed in more detail elsewhere. (See "Neuromuscular manifestations of systemic sclerosis (scleroderma)"). The following is a brief summary of the types of neurologic and muscle disorders that have been noted in case reports and series: • Cranial, entrapment, peripheral, cutaneous, autonomic neuropathies • Myopathy • Central nervous system involvement, including headache, seizures, stroke, vascular disease, radiculopathy, and myelopathy Genitourinary — SSc in men is very frequently associated with erectile dysfunction. This was illustrated in a survey that compared 43 SSc patients to 23 patients with rheumatoid arthritis (RA) [22]. Among the SSc patients, 81 percent had self-reported erectile dysfunction versus 48 percent of those with RA. While Raynaud phenomenon was more prevalent in SSc than in RA (86 versus 19 percent), it was not an independent predictor of erectile dysfunction. Women with SSc also have sexual dysfunction. This is related to decreased vaginal lubrication or constriction of the vaginal introitus. In one study, dyspareunia was present in 56 percent of 60 women with SSc [23]. Pregnancy — A detailed discussion of issues related to pregnancy in SSc is presented separately. (See "Systemic sclerosis (scleroderma) and pregnancy"). CANCER RISK — There have been several reports examining cancer in association with SSc [24-29]. The most significant association appears to be with lung cancer, which may account for approximately one-third of the cancers seen in SSc patients [26], however a significantly increased incidence was not noted in a population with a high background rate of lung cancer [29]. In a study of 632 Australian patients with SSc, 19 developed lung cancer [30]. Those who smoked were seven times as likely to develop cancer as those who did not. Pulmonary fibrosis and antitopoisomerase antibodies were not risk factors for lung cancer. The issue of malignancy in SSc was assessed in a population based, retrospective cohort analysis from Sweden performed between 1965 and 1983; 917 patients with SSc and 102 with localized scleroderma were compared to a cohort from the Swedish National Cancer Registry [24]. The ratio of cancers in SSc patients to expected cancers (the standardized incidence ratio, SIR) was 1.5 overall. Particular elevations were noted for lung cancer (SIR 4.9), skin cancer (SIR 4.2), hepatoma (SIR 3.3), and hematopoietic malignancies (SIR 2.3). In comparison to SSc, the cancer risk in patients with localized scleroderma was not different from that of the general population. A similar, modest increase in the overall risk of malignant disease (SIR 1.55) was also seen in a cohort of 769 patients seen from 1987-2002 [31]. There was, however, a marked increase in the risk of esophageal carcinoma (SIR 15.9 [95% CI 4.2-27.6]) and oropharyngeal carcinoma (SIR 9.63 [95%CI 2.97-16.3]). The cause of an increased cancer risk in SSc is not well understood. The association with lung and skin cancers suggests that sites of disease activity may be prone to malignant transformation. There are conflicting data on whether the presence of antibodies to topoisomerase-I (Scl-70) identifies a population of SSc patients who are more likely to have, or develop, cancer [32,33] In summary, the information available indicates a possible increased risk of malignancy in patients with SSc. The relationship cannot be considered proven due to the small number of patients. The author and editors wish to acknowledge contributions of Dr. Carol Black and Dr. Joseph Korn (deceased) to earlier versions of this topic review.